The potentially detrimental effects of concussion or mild traumatic brain injury (mTBI) are a major public health problem. Although the majority of mTBI patients recover within 1-2 weeks, a subpopulation takes weeks to months for full recovery and some report symptoms lasting years after the initial trauma. Thus, identification of clinically relevant factors that alter the brain's recovery after mTBI is an understudied, but much needed research area. Clinical investigations have reported that strenuous activity and exercise can lead to mild elevations in core and brain temperature. We now show that a relatively mild brain temperature elevation of only 39oC significantly aggravates neuropathological and cognitive outcome in two distinct models of mTBI as compared to normothermic mTBI. These observations suggest that small variations in brain temperature at or around the time of injury may influence the acute and long term traumatic consequences of mTBI. Novel preliminary results demonstrate that hyperthermia at the time of mTBI has profound effects on inflammatory, microvascular and hemodynamic perturbations. The goal of this proposal is to investigate the causal links between temperature- sensitive inflammatory and cerebrovascular responses and the emergence of structural and behavioral changes that may underlie the exacerbation of outcome after hyperthermic mTBI. Aim 1 will characterize the inflammatory responses to mTBI during normothermic or hyperthermic conditions. Flow cytometry will be used to characterize macrophage/microglia phenotypes and biomarker analysis including cytokine and chemokine signaling correlated with chronic cognitive outcomes. Complementary rat and transgenic models including CCL2 and caspase 1 knockout mice will clarify the role of inflammatory cell infiltration on triggering cytotoxic inflammation after hyperthermic mTBI. Aim 2 will focus on the microvascular permeability patterns following normothermic or hyperthermic mTBI in concert with tight junctional protein and endothelial adhesion molecule changes. The cellular identification of macrophage origins on cerebrovascular permeability and integrity will be correlated with inflammatory responses using ICAM-1 and MMP-9 transgenic models with light sheet fluorescence microscopy and 3D image visualization and quantitation. Because the hemodynamic state of the posttraumatic brain can influence secondary injury mechanisms after mTBI, Aim 3 will assess alterations in local cerebral blood flow and vascular reactivity using autoradiography and two-photon laser scanning microscopy. The underlying mechanisms of these hemodynamic responses will be tested using eNOS and iNOS knockout mice. Clinically relevant treatments including minocycline and progesterone targeting microglia and macrophage/endothelial interactions will be tested in these models of hyperthermic mTBI and concussion. Together, these studies will clarify the temperature-sensitive inflammatory and cerebrovascular events after hyperthermic mTBI, determine causal relationships of hyperthermia and secondary injury mechanisms and test clinically relevant interventions that are already in use in the clinic to reduce the devastating consequences of this common type of brain injury.